The mesolimbic dopamine system is a major neural substrate for reward, motivation and emotion. Dysfunction of this system has been linked to several psychiatric conditions including eating disorders, drug abuse, schizophrenia and depression. Recent studies suggest adiposity status and adipose-derived hormones, termed adipokines, modulate motivational and emotional responses. Adiponectin is the most abundant adipokine in circulation that can access the central nervous system. Our preliminary studies demonstrate that adiponectin induces activation of dopamine neurons in the ventral tegmental area (VTA) and that adiponectin receptor 1 (AdipoR1) is expressed in VTA dopamine neurons, suggesting that adiponectin functionally interacts with the mesolimbic dopamine system. The proposed studies in this project are to determine whether adiponectin regulates mesolimbic dopamine activity via interacting with AdipoR1 on dopamine neurons. To test this, we will first determine the effect of exogenous adiponectin on firing properties of VTA dopamine neurons and dopamine release in the nucleus accumbens, one of the major targets of the VTA dopamine neurons. Second, we will generate conditional knockout mice lacking AdipoR1 specifically in dopamine neurons and determine firing properties of VTA dopamine neurons as well as dopamine efflux in these mutant mice. These studies will provide novel information on the regulation of the mesolimbic dopamine pathway and new insights into dopamine-related processes in psychiatric illnesses especially those associated with metabolic syndrome such as obesity and diabetes. PUBLIC HEALTH RELEVANCE: Abnormal dopamine-related processes lead to aberrant reward, motivation and emotion in psychiatric disorders including eating disorders, drug addition, schizophrenia and depression. The proposed studies will enhance our understanding of how the mesolimbic dopamine system is regulated by the adipose-derived hormone adiponectin and will have clinical implications for psychiatric disorders associated with obesity and type 2 diabetes.